ERT IN JUVENILE AND ADULT GLYCOGENOSIS TYPE 2 Bruno Bembi – Giovanni Ciana – Andrea Dardis Unità di Malattie Metaboliche-Laboratorio di Malattie Rare Istituto.

ERT IN JUVENILE AND ADULT

GLYCOGENOSIS TYPE 2

Bruno Bembi – Giovanni Ciana – Andrea Dardis

Unità di Malattie Metaboliche-Laboratorio di Malattie Rare

Istituto per l’Infanzia “Burlo Garofolo”Trieste - Italy

Glycogenosis type II, Pompe diseaseGlycogenosis type II, Pompe diseaseor acid maltase deficiencyor acid maltase deficiency

• Autosomal recessive lysosomal Autosomal recessive lysosomal storagestorage diseasedisease

• Deficit of a-glucosidase or acid Deficit of a-glucosidase or acid maltasemaltase

• Glycogen accumulation within the Glycogen accumulation within the lysosomeslysosomes leads to enlargement of cardiac andleads to enlargement of cardiac and skeletal muscleskeletal muscle

Glycogenosis type IIGlycogenosis type IIPhenotypic continuumPhenotypic continuum

•Rapidly progressive muscle Rapidly progressive muscle

weakness weakness •Cardiomegaly and Cardiomegaly and

cardiomyopathy cardiomyopathy •Moderate hepatomegaly Moderate hepatomegaly •Macroglossia Macroglossia •Feeding difficulties Feeding difficulties •Frequent respiratory infectionsFrequent respiratory infections•Respiratory distressRespiratory distress•Delayed motor milestonesDelayed motor milestones•Markedly elevated CKMarkedly elevated CK•Rapidly progressive disease Rapidly progressive disease

coursecourse•no GAA activityno GAA activity

•Progressive muscular Progressive muscular

weakness weakness •No cardiac involvementNo cardiac involvement•Swallowing difficultySwallowing difficulty•Frequent respiratory Frequent respiratory

infectionsinfections•Respiratory distressRespiratory distress•Exercise intoleranceExercise intolerance•Elevated CKElevated CK•Moderate hepatomegalyModerate hepatomegaly•Residual GAA activityResidual GAA activity

Infantile onsetInfantile onset Late onsetLate onset

Molecular diagnosisMolecular diagnosis

Genomic DNA amplificationGenomic DNA amplification

•Screening frequent Screening frequent mutationsmutations• DHPLCDHPLC• Direct sequencingDirect sequencing

RT-PCR analysisRT-PCR analysis

Allele frequency in the Italian Allele frequency in the Italian infantile GSDII populationinfantile GSDII population

c.525delT(11.8%)

c.1064T>C(7.9%)

c.1655T>C(10.5%)

c.-32-13T>G (42.3%)

c.2237G>A (10.3%)

Allele frequency in the Italian Allele frequency in the Italian late onset GSDII populationlate onset GSDII population

Pt#Pt#

(sex)(sex)

AgeAge(years)(years)

First symptoms First symptoms notednoted

Mobility statusMobility status % % enzyme enzyme activityactivity

Respiratory Respiratory follow-upfollow-up

onsonsetet

DiagnoDiagnosissis

At At diagnosisdiagnosis

Follow-upFollow-up

11(F)(F)

1313 1414 Elevated CK, AST, Elevated CK, AST, ALTALT

Lower limb Lower limb weakness, Fatigueweakness, Fatigue

unrestricteunrestrictedd

With helpWith help 18 18 (M)(M)

Reduction of Reduction of pulmonary pulmonary functionfunction

22 (F)(F)

22 22 Elevated CK, AST, Elevated CK, AST, ALTALT

unrestricteunrestrictedd

unrestrictunrestricteded

NANA NormalNormal

33(F)(F)

3030 3131 Elevated CK, FatigueElevated CK, FatigueGeneralized Generalized weaknessweakness

unrestricteunrestrictedd

With With walker or walker or wheelchaiwheelchai

rr

4.3 4.3 (L)(L)

Respiratory Respiratory distressdistress

4 4 (M)(M)

1818 2727 Elevated CK, AST, Elevated CK, AST, ALTALT

Generalized Generalized weaknessweakness

unrestricteunrestrictedd

With helpWith help 1010 (M)(M)

non invasive non invasive ventilationventilation

55(F)(F)

3030 5252 Difficulty in walking Difficulty in walking up stepsup stepsFatigueFatigue

unrestricteunrestrictedd

With helpWith help absentabsent SupplementaSupplemental oxygenl oxygen

6 6 (M)(M)

2222 4646 Generalized Generalized weaknessweaknessFatigueFatigue

unrestricteunrestrictedd

With helpWith help 0.10.1 (L)(L)

Reduction of Reduction of pulmonary pulmonary functionfunction

77(M)(M)

3838 3838 Generalized Generalized weaknessweaknessFatigueFatigue

unrestricteunrestrictedd

With With difficultydifficulty

8 8 (L)(L)

Reduction of Reduction of pulmonary pulmonary functionfunction

88 (M)(M)

11 22 Elevated CK, AST, Elevated CK, AST, ALTALT

Muscular weaknessMuscular weakness

Impaired Impaired ambulatioambulatio

nn

With With wheelchaiwheelchai

rr

3.73.7 (M)(M)

non invasive non invasive ventilationventilation

99(M)(M)

11 1010 Elevated CK, AST, Elevated CK, AST, ALTALT

unrestricteunrestrictedd

unrestrictunrestricteded

0.020.02 (M)(M)

NormalNormal

Late onset c.-32-13T>G/ c.2237G>A genotype: Late onset c.-32-13T>G/ c.2237G>A genotype: clinical aspects clinical aspects

Enzyme Replacement Therapy

Myozyme dosage:20 mg/kg/every two weeks

Treatment period:12 to 24 months

•Juvenile forms: 7 (4 male, 3 female, age 12- 18 yrs)

•Adult forms: 6 (3 male, 3 female; age 27-54)

Clinical symptoms

Juveniles

Adults

Tracheotomy 1/7 2/6

Assisted ventilation 2/7 4/6

Severe hypotonia 2/7 5/6

Wheelchair 1/7 2/6

Reduced/impaired motility

4/7 6/6

Lordosis-scoliosis 3/7 5/6

Muscle pain 3/7 2/6

Headache 2/7 6/6Residual enzyme activity: 2.8-10%

Efficacy evaluation: clinical parameters

Juveniles

Adults

T0 T > 12 T0 T > 12

tracheotomy

1 - 2 -

Ventilatory support

2 1 4 4Reduced

time

PCO2 > 40 mmHg

5 2 6 4

Respiratory parameters

Efficacy evaluation: clinical parameters

Juveniles Adults

T 12 –24 T 12 –24

Muscular stenght

Improved: 7/7 Improved: 6/6

Fatigue Reduced: 4/4 Reduced: 5/6

Mobility Improved: 4/4 Improved: 6/6

Muscle pain 0/3 1/6

Headache 0/2 1/6

No need of life-saving procedures

6 Minute Wolking Test

0

100

200

300

400

500

600

700

800

900

t 0 t 3 t 6 t 9 t 12 t18

flb

apb

depf

dond

pm

pal

gn

Efficacy evaluation: laboratory and instrumental parameters

• CK, LDH, AST, ALT modifications

• Plasmatic creatinine

• Urinary oligosaccharides

• Muscular biopsy: histochemical and EM variations

• Imaging: muscular MNR

CPK

0

200

400

600

800

1000

1200

1400

t 0 t 3 t 6 t 9 t 12 t 18

flb

apb

depf

dond

pm

pal

gn

LDH

400

500

600

700

800

900

1000

1100

1200

1300

1400

t 0 t 3 t 6 t 9 t 12 t18

flb

apb

depf

dond

pm

pal

gn

ALT

0

50

100

150

200

250

300

350

t 0 t 3 t 6 t 9 t 12 t 18

flb

apb

depf

dond

pm

pal

gn

AST

0

50

100

150

200

250

300

t 0 t 3 t 6 t 9 t 12 t18

flb

apb

depf

dond

pm

pal

gn

Efficacia terapia: Wilks' Lambda F test p= 0.0021

Durata malattia: Wilks' Lambda F test p= 0.7605

RELAZIONE TRA INCREMENTO DEL 6 MINUTES WALKING TEST E DURATA DELLA MALATTIA A T0

RELAZIONE TRA INCREMENTO DEL 6mwt E SUO COMPLETAMENTO A T0

Efficacia terapia: p=0.0016

Influenza del completamento a T0: p= 0.4769

(Wilks' Lambda F test)

presente assente

p (two sided exact

binomial test )

Cefalea N % N %

T0 8 27.6 21 72.40.0122

T12 2 6.9 27 93.1

Dolore muscolare

T0 11 37.9 18 62.10.0020

T12 3 10.3 26 89.7

EFFICACIA DELLA ERT SULLA SINTOMATOLOGIA DOLOROSA (29 pazienti: 7 in età pediatrica, 22 adulti)

N pazienti

Incremento medio 95%CI range p

PCO2

T0 - T6 22 -2.5 -5.4 - 0.4 -19.6 - 7.0 0.2863

T6 – T12 23 -3.2 -5.5 -0.9 -15.6 - 9.0 0.0043

T0 - T12 25 -5.1 -8.7 -1.5 -28.5 - 3.9 0.0347

VC

T0 – T6 28 0.4 -3.5 - 4.4 -36.0 - 28 0.1516

T6 - T12 28 0.7 -1.3 - 2.8 -11.0 - 13 0.8318

TO - T12 29 1.1 -3.2 - 5.3 -38.5 - 27 0.7011

FEV 1

T0 – T6 20 0.23 0.07 - 0.37 -0.27 - 1.22 0.0044

T6 – T12 20 0.05 -0.05 - 0.15 -0.48 - 0.44 0.3593

T0 – T12 27 0.16 0.05 - 0.27 -0.33 - 0.72 0.0755

VARIAZIONI MEDIE DEI PARAMETRI RESPIRATORI, A 6 E 12 MESI

OPEN PROBLEMS IN PRE-ADOLESCENT SEVERE JUVENILE PATIENTS

IMAGING

IMAGING

FBL: born 04.1993

May 2006May 2007

FBL: born 04.1993

Jan 2005 March 2007 July 2007

Coordinamento Regionale Malattie Rare, AOU-UdineUnità di Malattie MetabolicheIRCCS Burlo Garofolo

Giovanni CianaAndrea DardisRoberta CariatiRiccardo Addobbati,Marco NevyjelSilvia DominissiniStefania Zampieri

Maria Gabriela Pittis

Unità di Pneumologia, Ospedale di Cattinara - Trieste

Marco ConfalonieriMaja DemsarMetka KodricRossana DellaPorta

Project supported Agenzia Ialiana del Farmaco and Genzyme Co.

•All patients and familiesAll patients and families

•AIGAIG